(3-cyano-1H-indol-7-yl)-[4-(4-fluorophenethyl)piperazin-1-yl]methanone (pruvanserin) is a highly selective 5-HT2A receptor antagonist useful in treating a number of 5-HT2A modulated disorders including depression and sleeping disorders, as described in WO 01/007435. Methods of preparing (3-cyano-1H-indol-7-yl)-[4-(4-fluorophenethyl)piperazin-1-yl]methanone and the hydrochloride salt are also disclosed therein. Further synthetic methods are described in WO 02/059092 and WO 05/009792.
Although (3-cyano-1H-indol-7-yl)-[4-(4-fluorophenethyl)piperazin-1-yl]-methanone is an effective pharmacological agent, the hydrochloride salt exhibits certain technical difficulties related to its polymorphic state. This salt's solid form converts from a single polymorphic form into a second, poorly crystalline, metastable polymorphic form upon compression during the manufacturing process. It is disadvantageous for a formulation to comprise a plurality of crystal forms of an active ingredient in that they may have different bioavailabilities and/or stability. Even slight variations in production conditions may compromise the reproducibility of the crystal form and therefore the performance of the formulated product. In addition, poorly crystalline materials are typically less desirable than highly crystalline materials because they are generally more difficult to handle during formulation processes.
Given the above, it is pharmacologically desirable and commercially advantageous to find a stable crystalline form that did not convert to other crystalline polymorphic forms during further processing, formulation and/or storage. Independently, it would be advantageous to find a crystalline form physically more conducive to formulation processing.